Grant Abstract

Abstract: DESCRIPTION (provided by applicant): Nephrolithiasis is a major public health problem of largely unknown cause. In the United States, total societal costs arising from urinary stone diagnosis, treatment, pain management, and lost wages total more than $2 billion annually. Kidney stones that contain more than 50% calcium oxalate account for approximately 75% of all kidney stone cases. An important strategy for reducing the risk of kidney stone formation is to decrease the amount of oxalate in urine. Urinary oxalate is derived about equally from both endogenous and dietary sources. There are currently no known means of decreasing endogenous oxalate synthesis in the majority of those afflicted. Thus, strategies to reduce dietary oxalate absorption represent an attractive alternative. Recent studies have indicated that a lack of Oxalobacter formigenes (OxF) colonization is a risk factor for stone formation. In addition, preliminary studies suggest that administering oral doses of OxF to patients with primary hyperoxaluria may decrease oxalate excretion. However, the precise mechanisms by which OxF colonization modifies the gut milieu, affects urinary oxalate and kidney stone formation, its natural history in humans, and the factors governing its persistence, population density and distribution have still not been clearly elucidated. The development of an animal model would facilitate our understanding of many of these areas. The utilization of mice has advantages including easy manipulation and control of environmental and dietary factors, and the ability for genetic modification which facilitates the study of the impact of specific genes. We have shown mice are readily colonized with administered OxF and retain colonization on low oxalate diets. This proposal aims to use a mouse model of OxF colonization to enhance our understanding of the impact of diet on oxalate handling and OxF biology and growth. The recent release of the annotated genomic sequence of OxF will for the first time permit the use of molecular approaches to answer compelling questions related to OxF physiology and host interactions. The model will also allow the potential effect of dietary oxalate and calcium on populations of gut bacteria other than OxF to be examined. If the specific aims are successfully completed they will provide valuable information about OxF biology, the factors that are important for OxF colonization, the role of enteric secretion in oxalate homeostasis, the role of other oxalate degrading bacteria in oxalate metabolism, and may identify new ways of modifying the gut milieu and stone risk. PUBLIC HEALTH RELEVANCE: Despite evidence demonstrating a lack of OxF colonization as a risk factor for calcium oxalate stone formation, very little is known about its biology, the factors that affect its growth and distribution, and its impact on oxalate handling. The purpose of this proposal is to use a mouse model of OxF colonization to facilitate our understanding of these poorly understood areas.